FCGR2C Polymorphisms Associated with HIV-1 Vaccine Protection Are Linked to Altered Gene Expression of Fc-γ Receptors in Human B Cells

Abstract

The phase III Thai RV144 vaccine trial showed an estimated vaccine efficacy (VE) to prevent HIV-1 infection of 31.2%, which has motivated the search for immune correlates of vaccine protection. In a recent report, several single nucleotide polymorphisms (SNPs) in FCGR2C were identified to associate with the level of VE in the RV144 trial. To investigate the functional significance of these SNPs, we utilized a large scale B cell RNA sequencing database of 462 individuals from the 1000 Genomes Project to examine associations between FCGR2C SNPs and gene expression. We found that the FCGR2C SNPs that associated with vaccine efficacy in RV144 also strongly associated with the expression of FCGR2A/C and one of them also associated with the expression of Fc receptor-like A (FCRLA), another Fc-γ receptor (FcγR) gene that was not examined in the previous report. These results suggest that the expression of FcγR genes is influenced by these SNPs either directly or in linkage with other causal variants. More importantly, these results motivate further investigations into the potential for a causal association of expression and alternative splicing of FCGR2C and other FcγR genes with the HIV-1 vaccine protection in the RV144 trial and other similar studies.

Fig 1. FCGR2C polymorphisms associate with FcγR gene expression in B cells in the European (EUR) population.

A. The boxplot shows the distribution of the expression (y-axis) of the last exon (hg19, chr1: 161487765–161489358) of FCGR2A in B cells from the 373 EUR individuals as quantified in [7], stratified by the genotypes (x-axis) of the SNP rs114945036. Individual expression levels are (horizontal line = median; bottom and top of box = 25^th and 75^th percentile). Expression in individuals is shown in blue dots. The significance of the association is indicated immediately above, which were mapped in [7] using a linear model implemented in Matrix eQTL [10]. B. Similar as A, for the SNP rs78603008. C. Similar as A, for the SNP rs138747765. D. Similar as A, for the SNP rs138747765 and the expression of the third exon (hg19, chr1:161680550–161680702) of FCRLA (Fc receptor-like A) in B cells.

Fig 2. FCRLA polymorphisms associate with FCRLA expression in human B cells.

A. Scatterplot of the eQTL p-values (-log10 scale) for the association of SNPs across the FcγR region with the expression of FCRLA as mapped in [7]. For simplicity, for each SNP only the smallest p-value from different levels of expression, i.e. exon, transcript, and gene, is shown. The green vertical bar indicates the location of the FCGR2C SNPs identified in [2]. The black horizontal line segments at the top indicate the positions of Refseq annotated FcγR genes, with the locations of FCGR2C and FCRLA labeled. B. Close view of SNPs around FCRLA in UCSC genome browser (hg19, chr1:161,670,571–161,688,007). The top track shows the genomic locations and the association p-values (-log10 scale) for those SNPs that passed the significance cutoff of FDR < 0.05 in their associations with the expression of FCRLA at different levels as reported in [7], i.e. exon, transcript, and gene. Highlighted in color cyan are SNPs with smallest p-values (also see S1 Table and S2 Table). The middle two horizontal tracks show the LD between each of the corresponding SNPs shown on top track and the SNP rs114945036. RefSeq gene annotation is shown at the bottom. C. Scatterplot of raw RNA-seq read counts (log2 scale) of RefSeq annotated FCGR2C (x-axis) and FCRLA (y-axis) in B cells from each of those 462 individuals. The number on the top-right corner shows the Pearson correlation coefficient.